P1042: SAFETY AND TOLERABILITY RESULTS FROM THE PHASE 3B FREEDOM TRIAL OF FEDRATINIB (FEDR), AN ORAL, SELECTIVE JAK2 INHIBITOR, IN PATIENTS WITH MYELOFIBROSIS (MF) PREVIOUSLY TREATED WITH RUXOLITINIB (RUX)
Authors: V. Gupta, A. Yacoub, S. Verstovsek, R. A. Mesa, C. N. Harrison, G. Barosi, J.-J. Kiladjian, H. J. Deeg, S. Fazal, L. Foltz, R. J. Mattison, C. B. Miller, V. Parameswaran, C. Hernandez, J. Zhang, M. Talpaz
Journal: HemaSphere (2022)

Background: FEDR is an oral, selective Janus kinase 2 (JAK2) inhibitor approved for treatment (Tx) of patients (pts) with MF, including those previously treated with RUX. In the single-arm, phase 2 JAKARTA2 trial in pts with MF resistant/intolerant to prior RUX, the most common adverse events (AEs) during FEDR Tx were gastrointestinal (GI) events. JAKARTA2 ended in 2013, when a temporary clinical hold was placed on FEDR due to suspected cases of Wernicke's encephalopathy (WE). The safety and efficacy of FEDR in pts with MF previously treated with RUX are being further evaluated in the ongoing, single-arm, phase 3b FREEDOM trial (NCT03755518), which includes prospective strategies for preventing or mitigating GI AEs, thiamine decreases, and potential WE. Aims: To assess the safety of FEDR and the effectiveness of AE mitigation strategies in the FREEDOM trial. Methods: Eligible pts had intermediate- or high-risk MF, platelets ≥50×109/L, and spleen volume ≥450cm3 by MRI/CT or palpable spleen ≥5 cm below the left costal margin. Pts must have received prior RUX for ≥3 mo, or for ≥28 d with development of red blood cell transfusion requirement (≥2 units/mo for 2 mo) or grade ≥3 thrombocytopenia, anemia, hematoma, or hemorrhage. All pts received FEDR 400 mg/d in continuous 28-d cycles. AE mitigation strategies include prophylactic and symptomatic use of anti-nausea/vomiting and anti-diarrheal Tx, thiamine supplementation, FEDR dosing modifications, and administration of FEDR with food. Results: In all, 34 pts were enrolled and 16 pts continued to receive FEDR at data cutoff (April 9, 2021). Reasons for FEDR discontinuation (D/C) in >1 pt were lack of efficacy (n=5), AEs (n=4), disease progression (n=2), pt decision (n=2), and to undergo transplant (n=2). Median FEDR Tx duration at cutoff was 28.3 (range, 1.6–101.3) wk; 14 (41%) pts had completed >12 cycles. At baseline (BL), median (range) age was 68.5 (49–82) y, time from MF diagnosis was 3.4 (0.1–17.4) y, and spleen size was 15 (3–31) cm. Most pts (62%) had primary MF, and all pts had received ≥3 mo of prior RUX; the most common reason for RUX D/C was loss of response/Tx failure (41%). During FEDR Tx, 22 (65%) pts received ondansetron and 11 (32%) pts received loperamide. GI AEs in >10% of pts were constipation (47%), diarrhea (35%), nausea (26%), abdominal pain (24%), and vomiting (18%). Nausea, vomiting, and diarrhea decreased as Tx continued. Most GI AEs were grade (G) 1/2 (including nausea, vomiting, and diarrhea) and there were no Tx-related G3/4 GI AEs. No pt required FEDR reduction, interruption, or D/C due to a Tx-related GI AE. Tx-related G3/4 AEs were reported in 11 (32%) pts, including anemia in 7 (21%) pts, and neutropenia, thrombocytopenia, and hyperkalemia in 2 (6%) pts each. At BL, 1 pt had thiamine below the 70 nmol/L lower limit of normal (LLN), which normalized before the pt received FEDR. During FEDR Tx, thiamine levels dropped below the LLN for 4 pts between cycles 2 and 3 (and for 1 pt at end of Tx); for these pts, levels returned to normal with thiamine supplementation and no FEDR interruption or reduction was required (Figure). Five other pts received prophylactic thiamine supplementation. There were no cases of WE. Image:Summary/Conclusion: FEDR was generally well tolerated in pts with MF previously treated with RUX. The frequency and severity of GI AEs were substantially lower in FREEDOM than in previous FEDR clinical trials, likely due to early implementation of GI prophylaxis. Thiamine decreases were uncommon and easily managed with routine monitoring and oral supplementation as needed.